It may be desirable to load a therapeutic compound onto or within particles of biomaterial for one or more of three main reasons: to carry, to store, or to sustain release. Drug carriers may have a specific function such as, for example, preventing degradation in the gut or to transport the molecules to a target organ or tissue. Storage in or on particles can occur by simple surface adsorption and can be limited by the specific surface area of the material. Alternatively, particles can be formed into porous agglomerates by gelation or sintering and the drug can be absorbed into the pore volume. Controlled release may occur by altering the binding affinity of the drug with the surface to control desorption, or a polymer layer or tortuosity provided by nanoporosity can act as a diffusion barrier or release may be mediated by dissolution of the ceramic particles themselves. Precipitation of inorganic bioceramic materials normally results in macro or microscale crystals with a correspondingly low specific surface area. A need exists for novel sustained release formulations.
There is considerable interest in the development of new materials that are capable of delivering a consistent and effective dose of therapeutic drugs and proteins in vivo. Problems with currently available materials include the requirement of a high-temperature processing step, which can damage heat sensitive molecules and a so called “burst-release” of the therapeutic agent following administration. Many different materials have been investigated for use as drug delivery matrices. However, choice of materials on offer to the biomaterials scientist is limited since any material that is used must be non-cytotoxic. One approach to the design of new biomaterials devices is to control the steps involved in the manufacturing process of already used materials to produce novel structures with improved efficiency in their given applications. Liu et al. attempted to form nanofiber networks which are capable of entrapping drugs and proteins in their meshes and consequently delivering a sustained dose of a particular drug. See “Creating New Supramolecular Materials by Architecture of Three-Dimensional Nanocrystal Fiber Networks,” J. Am. Chem. S. 124 (50): 15055-15063 (2002). Although structures appear to have been produced using L-DHL, they were not degradable in the body and consequently are of limited use as drug delivery matrices.
Condensed phosphates such as pyro- (P2O74−) and polyphosphates (PnO3n+1(n+2)) have been shown to play important roles in the control of biomineralisation and certain metabolic pathways. Pyrophosphates, for example, are known inhibitors of hydroxyapatite (HA) crystallisation and have been proposed to play an important role in the regulation of biomineralisation through interaction with alkaline phosphatase (ALP) and nucleoside triphosphate. It is thought that ALP catalyses the cleavage of the P—O—P bridge in the pyrophosphate molecule, which results in the production of PO43− and subsequent localised supersaturation leading to the precipitation of HA. There is evidence that suggests ALP is able to act on solid pyrophosphate salts, thus increasing the rate at which they may be dissolved. In one study, fluorescein isothiocyanate conjugated ALP was used to investigate whether bovine intestinal ALP absorbed to the surfaces of dicalcium pyrophosphate dihydrate crystals. See Shinozaki et al., “Calcium Pyrophosphate Dihydrate (CPPD) Crystal Dissolution by Alkaline-Phosphatase—Interaction of Alkaline-Phosphatase on Cppd Crystals,” J. of Rheumatology, 22(1) 117 (1995). This study described the localization of the enzyme on the surfaces of the crystals around etch-pits, which showed that the alkaline phosphatase was directly involved in calcium pyrophosphate dissolution. The apparent instability of P2O74− anions and salts in the presence of ALP (an enzyme synonymous with the formation of new bone), suggests that pyrophosphate salts have great promise as resorbable biomaterials and for localised release of phosphate ions and drugs.
Amorphous calcium pyrophosphates were first reported in the literature in 1963, but remained little researched until they were identified in a particular species of barnacle (Tetraclita squamosa). The amorphous granular deposits that were reported were thought to act as a sink for toxic ions in the water, as barnacles have no hepatopancreas. In a more recent study, one group attempted to synthesize these amorphous granules and found that in order to maintain the amorphous state of the granular deposits, ions such as Mn2+ had to be substituted into the structure of the granule. See Masala et al., “Modelling the Formation of Granules: the Influence of Manganese Ions on Calcium Pyrophosphate Precipitates,” Inorganica Chimica Acta, 339:366-372 (2002).